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Pharmaceutics Jul 2023Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low...
Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low solubility or permeability and limited controlled release from nanocarriers), which reduces their effectiveness in new medicines. Anticancer drugs have several major limitations, which include non-specificity, wide biological distribution, a short half-life, and systemic toxicity. Here, we investigate the potential of liposome-micelle-hybrid (LMH) carriers (i.e., drug-loaded micelles encapsulated within drug-loaded liposomes) to enhance the co-formulation and delivery of PTX and 5-FU, facilitating new delivery opportunities with enhanced chemotherapeutic performance. We focus on the combination of liposomes and micelles for co-delivery of PTX and 5_FU to investigate increased drug loading, improved solubility, and transport/permeability to enhance chemotherapeutic potential. Furthermore, combination chemotherapy (i.e., containing two or more drugs in a single formulation) may offer improved pharmacological performance. Compared with individual liposome and micelle formulations, the optimized PTX-5FU-LMH carriers demonstrated increased drug loading and solubility, temperature-sensitive release, enhanced permeability in a Caco-2 cell monolayer model, and cancer cell eradication. LMH has significant potential for cancer drug delivery and as a next-generation chemotherapeutic.
PubMed: 37514072
DOI: 10.3390/pharmaceutics15071886 -
Frontiers in Oncology 2020Paclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of...
PURPOSE
Paclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure-safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).
METHODS
Data from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.
RESULTS
The PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m, the estimated clearance of total plasma paclitaxel was 21.55 L h. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure-safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.
CONCLUSION
This PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure-safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.
PubMed: 33614470
DOI: 10.3389/fonc.2020.01731 -
AAPS PharmSciTech Feb 2018Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to...
Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to SKOV-3 cells at a molar ratio of 1 to 1 and in PTX ➔ GEM sequence. Liposomes were explored as a carrier of PTX and GEM combination. We optimized the drug loading in liposomes varying the preparation method and co-encapsulated PTX and GEM in a single liposome preparation maintaining the maximum loading efficiency of each drug. However, drug release kinetics from the co-loaded liposomes (LpPG) was suboptimal because of the detrimental effect of PTX on GEM-release control. Instead, a mixture of LpP and LpG, which were separately optimized according to the desired release kinetics, achieved a greater cytotoxic effect than LpPG, due to the attenuation of GEM release relative to PTX. This study illustrates that co-encapsulation in a single carrier is not always desirable for the delivery of drug combinations, when the activity depends on the dosing sequence. These combinations may benefit from the mixed liposome approach, which offers greater flexibility in controlling the ratio and release kinetics of component drugs.
Topics: Cell Line, Tumor; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Liberation; Humans; Liposomes; Paclitaxel; Gemcitabine
PubMed: 28971370
DOI: 10.1208/s12249-017-0877-z -
European Journal of Cardio-thoracic... Jul 2016Nanotechnology is an emerging, rapidly evolving field with the potential to significantly impact care across the full spectrum of cancer therapy. Of note, several recent... (Review)
Review
Nanotechnology is an emerging, rapidly evolving field with the potential to significantly impact care across the full spectrum of cancer therapy. Of note, several recent nanotechnological advances show particular promise to improve outcomes for thoracic surgical patients. A variety of nanotechnologies are described that offer possible solutions to existing challenges encountered in the detection, diagnosis and treatment of lung cancer. Nanotechnology-based imaging platforms have the ability to improve the surgical care of patients with thoracic malignancies through technological advances in intraoperative tumour localization, lymph node mapping and accuracy of tumour resection. Moreover, nanotechnology is poised to revolutionize adjuvant lung cancer therapy. Common chemotherapeutic drugs, such as paclitaxel, docetaxel and doxorubicin, are being formulated using various nanotechnologies to improve drug delivery, whereas nanoparticle (NP)-based imaging technologies can monitor the tumour microenvironment and facilitate molecularly targeted lung cancer therapy. Although early nanotechnology-based delivery systems show promise, the next frontier in lung cancer therapy is the development of 'theranostic' multifunctional NPs capable of integrating diagnosis, drug monitoring, tumour targeting and controlled drug release into various unifying platforms. This article provides an overview of key existing and emerging nanotechnology platforms that may find clinical application in thoracic surgery in the near future.
Topics: Ablation Techniques; Antineoplastic Agents; Dendrimers; Drug Delivery Systems; Gene Transfer Techniques; Humans; Liposomes; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Micelles; Nanoparticles; Nanotechnology; Nanotubes, Carbon; Quantum Dots; Surgery, Computer-Assisted; Thoracic Surgical Procedures
PubMed: 26843431
DOI: 10.1093/ejcts/ezw002 -
Chinese Clinical Oncology Dec 2018Epithelial ovarian cancer (EOC) is a common malignant disease, which remains asymptomatic for a prolonged period of time and is usually diagnosed at advanced stages.... (Review)
Review
Epithelial ovarian cancer (EOC) is a common malignant disease, which remains asymptomatic for a prolonged period of time and is usually diagnosed at advanced stages. Cytoreductive surgery is a backbone of EOC treatment. Wherever possible, EOC patients are subjected to primary debulking surgery (PDS) with the aim to remove all visible tumor lumps. Some patients cannot undergo PDS due to extensive disease spread and/or high risk of perioperative morbidity, therefore they are subjected to neoadjuvant chemotherapy (NACT) before the surgery. Therapy given before surgery or as adjuvant treatment usually consists of combination of carboplatin and paclitaxel. Gemcitabine, topotecan, pegylated liposomal doxorubicin and poly ADP ribose polymerase inhibitors (PARPi) are commonly used for the management of EOC relapses. Consideration of BRCA1/2 germ-line and somatic status is getting increasingly important for the proper treatment planning.
Topics: Cytoreduction Surgical Procedures; Female; Humans; Neoadjuvant Therapy; Ovarian Neoplasms
PubMed: 30509078
DOI: 10.21037/cco.2018.10.06 -
Translational Cancer Research Sep 2019To evaluate the efficacy and safety of liposome-paclitaxel (L-PTX)/L-PTX plus S-1 in advanced gastric cancer patients with poor performance status (PS).
BACKGROUND
To evaluate the efficacy and safety of liposome-paclitaxel (L-PTX)/L-PTX plus S-1 in advanced gastric cancer patients with poor performance status (PS).
METHODS
We performed this retrospective study on 17 advanced gastric cancer patients with poor PS [rated as ≥2 based on the Eastern Cooperative Oncology Group (ECOG) scale] who underwent the following chemotherapy regimen: (I) L-PTX single-agent: L-PTX 60-80 mg/m given on days 1 and 8, in a 21-day cycle; (II) timed sequential (TS) regimen: L-PTX 60-80 mg/m given on days 1 and 8. S-1, 40-60 mg/m twice a day on days 1-14, in a 21-day cycle. Initially, some patients could not tolerate the 2-drug combination chemotherapy regimen, only L-PTX single-agent was given. After the patient's physical condition was improved, plus S-1 was also given.
RESULTS
A total of 17 patients were studied. No complete response (CR) or partial response (PR) were observed in six patients, accounting for 35.29% (6/17). Stable disease (SD) was observed in five patients, accounting for 29.41% (5/17), and progressive disease (PD) in 6, accounting for 35.29% (6/17). The objective response and disease control rates were 35.29% (6/17) and 64.71% (11/17), respectively. The median progression-free survival (PFS) and median overall survival (OS) were 6.50 months [95% confidence interval (CI): 4.81-8.20] and 13.00 months (95% CI: 0.00-33.65), respectively. The most common hematological toxicities were neutropenia and anemia.
CONCLUSIONS
L-PTX/L-PTX plus S-1 in the treatment of advanced gastric cancer patients with poor PS can prolong the patients' PFS and OS, and the toxicity is tolerable.
PubMed: 35116918
DOI: 10.21037/tcr.2019.08.17 -
Cancer Dec 2019The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to... (Review)
Review
The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Neoplasm Recurrence, Local
PubMed: 31967680
DOI: 10.1002/cncr.32500 -
International Journal of Nanomedicine 2022Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer....
PURPOSE
Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages.
METHODS
ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP.
RESULTS
Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs.
CONCLUSION
ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.
Topics: Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Drug Delivery Systems; Estrone; Female; Humans; Liposomes; Mice; Mice, Inbred ICR; Ovarian Neoplasms; Paclitaxel; Polyethylene Glycols; Tissue Distribution
PubMed: 35836838
DOI: 10.2147/IJN.S362263 -
Evidence-based Complementary and... 2022The aim of this study is to investigate the effect of paclitaxel combined with doxorubicin hydrochloride liposome injection (DHLI) in the treatment of osteosarcoma and...
OBJECTIVE
The aim of this study is to investigate the effect of paclitaxel combined with doxorubicin hydrochloride liposome injection (DHLI) in the treatment of osteosarcoma and the MRI changes before and after treatment.
METHODS
A total of 108 osteosarcoma patients treated in our hospital (January 2020-April 2022) were selected to carry out a single-center retrospective study. Among them, 54 patients receiving the combination chemotherapy (MDT) with high-dose methotrexate, ifosfamide, cisplatin, and ADM were selected as the control group (COG), while 54 patients receiving MDT with high-dose methotrexate, ifosfamide, cisplatin, paclitaxel, and DHLI were chosen as the study group (STG). The COG and STG had the same dose intensity and chemotherapy cycles, and clinical and MRI evaluations were performed after treatment.
RESULTS
The evaluation of postoperative clinical efficacy showed that the disease control rate (DCR) of the STG was markedly higher than that of the COG ( < 0.05). The incidence of cardiac toxicity was remarkably lower in the STG than that in the COG ( < 0.05), with no between-group differences in the incidence of fever, abnormal liver function, myelosuppression, stomatitis, and alopecia ( > 0.05). Obvious differences were found in the semiquantitative parameters of MRI in the STG before and after chemotherapy ( < 0.05) and were also found in the SI, TTP, SEE, PPE, WOR, and values in the COG before and after chemotherapy ( < 0.05). After chemotherapy, statistical differences were observed in the semiquantitative parameters of MRI between the two groups, with lower parameters such as Slope, SI, SEE, and values and higher parameters such as TTP, PPE, and WOR values in the STG than those in the COG ( < 0.05).
CONCLUSION
Paclitaxel combined with DHLI has definite efficacy in osteosarcoma chemotherapy, which is conducive to narrowing the lesion, controlling the disease, and reducing the occurrence of cardiac-related risk events. In addition, the semiquantitative parameters of dynamic contrast-enhanced MRI (DCE-MRI) have a high predictive value for the efficacy of chemotherapy, which can reflect the degree of tumor necrosis and contribute to a timely and objective assessment of the efficacy of osteosarcoma chemotherapy.
PubMed: 35942377
DOI: 10.1155/2022/5651793 -
Frontiers in Pharmacology 2024Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of...
Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of regional chemotherapy using paclitaxel, albumin-paclitaxel, and liposome-encapsulated albumin-paclitaxel via subserosal injection in rat models employing nuclear medicine and molecular imaging technology. Nine Sprague Dawley rats were divided into three groups: paclitaxel ( = 3), albumin-paclitaxel nano-particles (APNs; = 3), and liposome-encapsulated APNs ( = 3). [I]Iodo-paclitaxel ([I]I-paclitaxel) was synthesized by conventional electrophilic radioiodination using -butylstannyl substituted paclitaxel as the precursor. Albumin-[I]iodo-paclitaxel nanoparticles ([I]APNs) were prepared using a desolvation technique. Liposome-encapsulated APNs (L-[I]APNs) were prepared by thin-film hydration using DSPE-PEG2000, HSPC, and cholesterol. The rats in each group were injected with each test drug into the subserosa of the stomach antrum. After predetermined times (30 min, 2, 4, 8 h, and 24 h), molecular images of nuclear medicine were acquired using single-photon emission computed tomography/computed tomography. Paclitaxel, APNs, and L-APNs showed a high cumulative distribution in the stomach, with L-APNs showing the largest area under the curve. Most drugs administered via the gastric subserosal route are distributed in the stomach and intestines, with a low uptake of less than 1% in other major organs. The time to reach the maximum concentration in the intestine for L-APNs, paclitaxel, and APNs was 6.67, 5.33, and 4.00 h, respectively. These preliminary results imply that L-APNs have the potential to serve as a novel paclitaxel preparation method for the regional treatment of gastric cancer.
PubMed: 38904000
DOI: 10.3389/fphar.2024.1381406